What Is DPD Deficiency, and Why Does It Matter Before 5-FU or Capecitabine Chemotherapy?
In this article
New FDA Safety Warning
On January 24, 2025, the US Food and Drug Administration (FDA) highlighted risks associated with dihydropyrimidine dehydrogenase (DPD) deficiency in relation to fluorouracil (5-FU) or capecitabine treatment through important product-labeling updates intended to inform patients and physicians before these medicines are used.
The labeling states that DPD deficiency may be associated with serious, potentially fatal adverse effects. Oncologists should particularly discuss these risks and genetic testing options with patients.
What Is DPD Deficiency, and Why Is It Important?
Fluoropyrimidines, including 5-FU and capecitabine, are widely used cancer medicines. The DPD enzyme, encoded by DPYD, is crucial for metabolizing more than 80% of 5-FU. Certain homozygous or compound heterozygous DPYD variants may cause complete or near-complete loss of enzyme activity.
How Common Is DPD Deficiency?
DPD deficiency is uncommon but may have important clinical consequences. Frequency varies with genetic variant prevalence and ancestry.
-
Complete DPD Deficiency:
- In the general population, complete deficiency is very rare. It causes severe problems with fluoropyrimidine metabolism and a high toxicity risk.
- Estimated frequency: 1:10,000 to 1:20,000 individuals.
-
Partial DPD Deficiency:
- Partial deficiency is more common and increases toxicity risk, although the extent varies between people.
- In Western populations, estimated frequency is approximately 3-5% of individuals.
-
Distribution by Genetic Variant:
- In people of European ancestry, DPD deficiency-associated DPYD*2A and other common variants occur in 3-5%.
- Other variants, such as rs75017182, are more frequent in people of African ancestry.
- These variants are less frequent in populations of Asian ancestry.
What Are the Symptoms?
DPD deficiency may increase the risk of serious toxic reactions, including:
-
Mucosal inflammation (mucositis and mouth sores)
-
Diarrhea
-
Neutropenia (low white blood cells)
-
Neurotoxicity
Effects can be very severe with complete deficiency, but risk is also high with partial deficiency.
FDA Updates and Project Renewal
Through its Oncology Center of Excellence's “Project Renewal,” the FDA added important DPD information to capecitabine (Kapeda, Xeltabin) and 5-FU labeling:
-
Scope:
-
Capecitabine or 5-FU is not recommended in complete DPD deficiency. No safe dose has been established.
-
No specific dose is recommended for partial deficiency.
-
-
Physicians' Responsibilities:
-
Inform patients about serious adverse effects associated with DPD deficiency.
-
Discuss the importance and options for genetic testing.
-
Consider testing before treatment to prevent serious toxicity.
-
-
Symptoms and Monitoring:
-
Warn patients about mucositis, diarrhea, neutropenia, and neurotoxicity, and advise immediate contact with a physician if they occur.
-
Early symptoms or unusually severe reactions may indicate complete deficiency and require discontinuation.
-
The Role of Genetic Testing
Four DPYD variants associated with reduced activity have been identified in White populations, and one in people of African ancestry. Testing is therefore important for assessing individual risks.
The FDA's Call
The FDA invites patients and healthcare providers to report capecitabine and 5-FU adverse effects through MedWatch. Emerging evidence and implications of DPD deficiency will continue to be evaluated.
Conclusion
DPD deficiency is a critical condition potentially associated with serious or fatal fluoropyrimidine toxicity. Greater physician awareness and detailed patient discussions are essential for safety. Wider testing and implementation of labeling warnings are important steps toward protecting health and quality of life.
Sources
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.